A major objective of this project will be to improve the therapy of acute myelocytic leukemia, especially during initial treatment or after relapse. In pursuing this goal, we will attempt to characterize and to enhance if possible any synergistic effects of two-drug combinations. We will also explore the extent to which synergistic or antagonistic lethal effects can be attributed to drug-induced cell cycle redistribution or recruitment of resting cells to proliferate. Bone marrow and blood samples will be obtained prior to and at intervals during and after drug administration. Possible kinetic effects of the drugs will be monitored by the use of flow cytofluorometry of DNA determinations for observation of chromatin changes as inferred from altered fluorescence at low dye/DNA ratios. Other parameters, such as mitotic and tritiated thymidine labeling indices, and light scattering intensity of unstained cells, will also be measured. Closely coordinated with these in vivo investigations will be analogous studies in cell culture, using asynchronous exponental phase cells, highly synchronous populations, or high density plateau phase cells. Highly synchronous cells will be used to determine both drug lethality and cell cycle progression delay as a function of cell cycle phase. Plateau phase cells will be employed to study both lethality and the possible recruitment of resting cells by cytosine arabinoside or other drugs. A mathematical model will be utilized to estimate more accurately the drug responses of cells with respect to cell maturity even when some loss of synchrony has occurred.